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Pharmaceutical Research

, Volume 29, Issue 1, pp 306–318 | Cite as

Extending Residence Time and Stability of Peptides by Protected Graft Copolymer (PGC) Excipient: GLP-1 Example

  • Gerardo M. CastilloEmail author
  • Sandra Reichstetter
  • Elijah M. BolotinEmail author
Research Paper

ABSTRACT

Purpose

To determine whether a Protected Graft Copolymer (PGC) containing fatty acid can be used as a stabilizing excipient for GLP-1 and whether PGC/GLP-1 given once a week can be an effective treatment for diabetes.

Methods

To create a PGC excipient, polylysine was grafted with methoxypolyethyleneglycol and fatty acid at the epsilon amino groups. We performed evaluation of the binding of excipient to GLP-1, the DPP IV sensitivity of GLP-1 formulated with PGC as the excipient, the in vitro bio-activity of excipient-formulated GLP-1, the in vivo pharmacokinetics of excipient-formulated GLP-1, and the efficacy of the excipient-formulated GLP-1 in diabetic rats.

Results

We showed reproducible synthesis of PGC excipient, high affinity binding of PGC to GLP-1, slowed protease degradation of excipient-formulated GLP-1, and that excipient-formulated GLP-1 induced calcium influx in INS cells. Excipient-formulated GLP-1 stays in the blood for at least 4 days. When excipient-formulated GLP-1 was given subcutaneously once a week to diabetic ZDF rats, a significant reduction of HbA1c compared to control was observed. The reduction is similar to diabetic ZDF rats given exendin twice a day.

Conclusions

PGC can be an ideal in vivo stabilizing excipient for biologically labile peptides.

KEY WORDS

diabetes glucagon like peptide peptide excipient protected graft copolymer 

ABBREVIATIONS

DPP IV

dipeptidyl peptidase IV

GLP-1

Glucagon-like peptide-1

HbA1c

glycosylated hemoglobin

PEGylation

poly(ethylene glycol) conjugation

PGC

protected graft copolymer

Notes

ACKNOWLEDGMENTS & DISCLOSURES

This work was supported by the SBIR Grant #DK069727 from National Institute of Diabetes and Digestive and Kidney diseases of the National Institute of Health. The authors thank Ms. Cynthia Jones, Ms. Akiko Nishimoto-Ashfield, and Ms. Marisa Robinson for assistance with the manuscript.

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.PharmaIN CorporationSeattleUSA

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